The Chemistry of Drugs to Treat Candida albicans

2019 ◽  
Vol 19 (28) ◽  
pp. 2554-2566 ◽  
Author(s):  
Aurelio Ortiz ◽  
Estibaliz Sansinenea
Keyword(s):  
Candida Species ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Drug Classes ◽  
Life Threatening ◽  
Antifungal Substances ◽  
High Level ◽  
Systemic Infections ◽  
New Compounds ◽  
Level Resistance

Background:: Candida species are in various parts of the human body as commensals. However, they can cause local mucosal infections and, sometimes, systemic infections in which Candida species can spread to all major organs and colonize them. Objective:: For the effective treatment of the mucosal infections and systemic life-threatening fungal diseases, a considerably large number of antifungal drugs have been developed and used for clinical purposes that comprise agents from four main drug classes: the polyenes, azoles, echinocandins, and antimetabolites. Method: : The synthesis of some of these drugs is available, allowing synthetic modification of the molecules to improve the biological activity against Candida species. The synthetic methodology for each compound is reviewed. Results: : The use of these compounds has caused a high-level resistance against these drugs, and therefore, new antifungal substances have been described in the last years. The organic synthesis of the known and new compounds is reported. Conclusion: : This article summarizes the chemistry of the existing agents, both the old drugs and new drugs, in the treatment of infections due to C. albicans, including the synthesis of the existing drugs.

scholarly journals NON TYPHOIDAL SALMONELLOSIS IN A PATIENT WITH ULCERATIVE COLITIS -MULTI DRUG RESISTANT SALMONELLA TYPHIMURIUM AND MOLECULAR CHARACTERISATION OF RESISTANT GENES A CASE REPORT

2020 ◽  
Vol 9 (11) ◽  
pp. 717-721
Author(s):  
Secunda R. ◽  
◽  
Radhika Katragadda ◽  
Ramani C.P. ◽  
Sudha N. ◽  
...  
Keyword(s):  
Case Report ◽  
Salmonella Typhimurium ◽  
Enteric Bacteria ◽  
Diffusion Method ◽  
Ground Meat ◽  
Animal Products ◽  
Diffuse Abdominal Pain ◽  
Life Threatening ◽  
High Level ◽  
Level Resistance

Background: Non typhoidal Salmonellosis are widely prevalent in developed as well as developing countries caused mostly by S.typhimurium and S enteritidis. Transmission of NTS to humans can occur by many routes including consumption of food of animal products mainly egg, poultry, undercooked ground meat and dairy products. Gastroenteritis is the most frequent manifestation, while less frequently may lead to complication like Bacteremia and Septicemia. Case summary: This is a case report of a 69 years old male admitted in Medical Gastro Enterology department with complaints of loose stools about 15-20 episodes per day with blood in some episodes and associated with diffuse abdominal pain. Culture of the stool sample detected Salmonella typhimurium which was sensitive to Cotrimoxazole & Azithromycin and resistant to Ciprofloxacin, Ampicillin & Ceftriaxone by disc diffusion method. Genotyping was done by PCR and this showed the presence of CTX-M and TEM genes. Conclusion: Non Typhoidal Salmonellae though causes self-limiting Gastroenteritis but in immunosuppressed individual it leads to focal infections & life-threatening bacteremia. The isolate from stool showed high level resistance and this could be due to increased usage of antibiotics in poultry and transfer of plasmids carrying resistance genes among enteric bacteria.

scholarly journals Plasmodium falciparum Resistance to a Lead Benzoxaborole Due to Blocked Compound Activation and Altered Ubiquitination or Sumoylation

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Kirthana M. V. Sindhe ◽  
Wesley Wu ◽  
Jenny Legac ◽  
Yong-Kang Zhang ◽  
Eric E. Easom ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Stress Responses ◽  
Mechanisms Of Action ◽  
Antimalarial Drugs ◽  
New Drugs ◽  
Loss Of Function ◽  
Content Type ◽  
High Level ◽  
Level Resistance

ABSTRACT New antimalarial drugs are needed. The benzoxaborole AN13762 showed excellent activity against cultured Plasmodium falciparum, against fresh Ugandan P. falciparum isolates, and in murine malaria models. To gain mechanistic insights, we selected in vitro for P. falciparum isolates resistant to AN13762. In all of 11 independent selections with 100 to 200 nM AN13762, the 50% inhibitory concentration (IC50) increased from 18–118 nM to 180–890 nM, and whole-genome sequencing of resistant parasites demonstrated mutations in prodrug activation and resistance esterase (PfPARE). The introduction of PfPARE mutations led to a similar level of resistance, and recombinant PfPARE hydrolyzed AN13762 to the benzoxaborole AN10248, which has activity similar to that of AN13762 but for which selection of resistance was not readily achieved. Parasites further selected with micromolar concentrations of AN13762 developed higher-level resistance (IC50, 1.9 to 5.0 μM), and sequencing revealed additional mutations in any of 5 genes, 4 of which were associated with ubiquitination/sumoylation enzyme cascades; the introduction of one of these mutations, in SUMO-activating enzyme subunit 2, led to a similar level of resistance. The other gene mutated in highly resistant parasites encodes the P. falciparum cleavage and specificity factor homolog PfCPSF3, previously identified as the antimalarial target of another benzoxaborole. Parasites selected for resistance to AN13762 were cross-resistant with a close analog, AN13956, but not with standard antimalarials, AN10248, or other benzoxaboroles known to have different P. falciparum targets. Thus, AN13762 appears to have a novel mechanism of antimalarial action and multiple mechanisms of resistance, including loss of function of PfPARE preventing activation to AN10248, followed by alterations in ubiquitination/sumoylation pathways or PfCPSF3. IMPORTANCE Benzoxaboroles are under study as potential new drugs to treat malaria. One benzoxaborole, AN13762, has potent activity and promising features, but its mechanisms of action and resistance are unknown. To gain insights into these mechanisms, we cultured malaria parasites with nonlethal concentrations of AN13762 and generated parasites with varied levels of resistance. Parasites with low-level resistance had mutations in PfPARE, which processes AN13762 into an active metabolite; PfPARE mutations prevented this processing. Parasites with high-level resistance had mutations in any of a number of enzymes, mostly those involved in stress responses. Parasites selected for AN13762 resistance were not resistant to other antimalarials, suggesting novel mechanisms of action and resistance for AN13762, a valuable feature for a new class of antimalarial drugs.

scholarly journals An Overview on Conventional and Non-Conventional Therapeutic Approaches for the Treatment of Candidiasis and Underlying Resistance Mechanisms in Clinical Strains

2020 ◽  
Vol 6 (1) ◽  
pp. 23 ◽  
Author(s):  
Sara B. Salazar ◽  
Rita S. Simões ◽  
Nuno A. Pedro ◽  
Maria Joana Pinheiro ◽  
Maria Fernanda N. N. Carvalho ◽  
...  
Keyword(s):  
Candida Species ◽  
Fungal Infections ◽  
Resistance Mechanisms ◽  
Antifungal Drugs ◽  
Mortality And Morbidity ◽  
Synthetic Chemicals ◽  
Mucosal Surfaces ◽  
Life Threatening ◽  
Resistant Strains ◽  
Novel Approaches

Fungal infections and, in particular, those caused by species of the Candida genus, are growing at an alarming rate and have high associated rates of mortality and morbidity. These infections, generally referred as candidiasis, range from common superficial rushes caused by an overgrowth of the yeasts in mucosal surfaces to life-threatening disseminated mycoses. The success of currently used antifungal drugs to treat candidiasis is being endangered by the continuous emergence of resistant strains, specially among non-albicans Candida species. In this review article, the mechanisms of action of currently used antifungals, with emphasis on the mechanisms of resistance reported in clinical isolates, are reviewed. Novel approaches being taken to successfully inhibit growth of pathogenic Candida species, in particular those based on the exploration of natural or synthetic chemicals or on the activity of live probiotics, are also reviewed. It is expected that these novel approaches, either used alone or in combination with traditional antifungals, may contribute to foster the identification of novel anti-Candida therapies.

The antifungal activities and biological consequences of BMVC-12C-P, a carbazole derivative against Candida species

2019 ◽  
Vol 58 (4) ◽  
pp. 521-529
Author(s):  
Mandy Shen ◽  
Pei-Tzu Li ◽  
Yan-Jia Wu ◽  
Ching-Hsuan Lin ◽  
Eric Chai ◽  
...  
Keyword(s):  
Candida Species ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
New Drugs ◽  
High Morbidity ◽  
Carbazole Derivative ◽  
Antifungal Activities ◽  
Development Of Resistance ◽  
Fluconazole Resistant ◽  
Candida Infections

Abstract Fungal infections, particularly Candida species, have increased worldwide and caused high morbidity and mortality rates. The toxicity and development of resistance in present antifungal drugs justify the need of new drugs with different mechanism of action. BMVC-12C-P, a carbazole-type compound, has been found to dysfunction mitochondria. BMVC-12C-P displayed the strongest antifungal activities among all of the BMVC derivatives. The minimal inhibitory concentration (MIC) of BMVC-12C-P against Candida species ranged from 1 to 2 μg/ml. Fluconazole-resistant clinical isolates of Candida species were highly susceptible to BMVC-12C-P. The potent fungicidal activity of BMVC-12C-P relates to its impairing mitochondrial function. Furthermore, we found that the hyphae growth and biofilm formation were suppressed in C. albicans survived from BMVC-12C-P treatment. This study demonstrates the potential of BMVC-12C-P as an antifungal agent for treating Candida infections.

scholarly journals Tunicamycin Potentiates Antifungal Drug Tolerance via Aneuploidy in Candida albicans

mBio ◽  
2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Feng Yang ◽  
Vladimir Gritsenko ◽  
Yaniv Slor Futterman ◽  
Lu Gao ◽  
Cheng Zhen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Drug Efficacy ◽  
Drug Tolerance ◽  
Tolerance Limit ◽  
Antifungal Drug ◽  
Content Type ◽  
Drug Classes ◽  
Life Threatening ◽  
Systemic Infections

Candida albicans is a prevalent human fungal commensal and also a pathogen that causes life-threatening systemic infections. Treatment failures are frequent because few therapeutic antifungal drug classes are available and because drug resistance and tolerance limit drug efficacy.

scholarly journals In Vitro Activities of Caspofungin Compared with Those of Fluconazole and Itraconazole against 3,959 Clinical Isolates of Candida spp., Including 157 Fluconazole-Resistant Isolates

2003 ◽  
Vol 47 (3) ◽  
pp. 1068-1071 ◽  
Author(s):  
M. A. Pfaller ◽  
D. J. Diekema ◽  
S. A. Messer ◽  
R. J. Hollis ◽  
R. N. Jones
Keyword(s):  
Antifungal Drugs ◽  
Broth Microdilution ◽  
Candida Spp ◽  
Medical Centers ◽  
Spectrum Activity ◽  
Fluconazole Resistant ◽  
High Level ◽  
Level Resistance ◽  
Broad Spectrum Activity

ABSTRACT Caspofungin is an echinocandin antifungal agent with broad-spectrum activity against Candida and Aspergillus spp. The in vitro activities of caspofungin against 3,959 isolates of Candida spp. obtained from over 95 different medical centers worldwide were compared with those of fluconazole and itraconazole. The MICs of the antifungal drugs were determined by broth microdilution tests performed according to the NCCLS method using RPMI 1640 as the test medium. Caspofungin was very active against Candida spp. (MIC at which 90% of the isolates were inhibited [MIC90], 1 μg/ml; 96% of MICs were ≤2 μg/ml). Candida albicans, C. dubliniensis, C. tropicalis, and C. glabrata were the most susceptible species of Candida (MIC90, 0.25 to 0.5 μg/ml), and C. guilliermondii was the least susceptible (MIC90, >8 μg/ml). Caspofungin was very active against Candida spp., exhibiting high-level resistance to fluconazole and itraconazole (99% of MICs were ≤1 μg/ml). These results provide further evidence for the spectrum and potency of caspofungin activity against a large and geographically diverse collection of clinically important isolates of Candida spp.

scholarly journals Multiresistant Neisseria gonorrhoeae: a new threat in second decade of the XXI century

2019 ◽  
Vol 209 (2) ◽  
pp. 95-108 ◽  
Author(s):  
Beata Młynarczyk-Bonikowska ◽  
Anna Majewska ◽  
Magdalena Malejczyk ◽  
Grażyna Młynarczyk ◽  
Sławomir Majewski
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Clonal Complex ◽  
Etiologic Agent ◽  
New Drugs ◽  
Sexually Transmitted ◽  
Treatment Regimens ◽  
Resistant Strains ◽  
High Level ◽  
First Time ◽  
Level Resistance

AbstractNeisseria gonorrhoeae is an etiologic agent of gonorrhoea, one of the most common sexually transmitted diseases caused by bacteria. For many years, infections caused by N. gonorrhoeae were considered to be relatively easy to treat; however, resistance has emerged successively to all therapeutic agents used in treatment of the disease, e.g., penicillin, ciprofloxacin or azithromycin. Currently, the global problem is the emergence and a threat of spread of N. gonorrhoeae strains resistant to extended-spectrum cephalosporins (ESC), such as injectable ceftriaxone and oral-used cefixime. Especially, dangerous are multi-resistant strains resistant simultaneously to ESC and azithromycin. Three strains with high-level resistance to azithromycin and resistant to ESC were first time isolated in 2018. Moreover, in 2018, the first ESBL was described in N. gonorrhoeae and that makes the threat of appearing the ESBL mechanism of resistance in N. gonorrhoeae more real, even though the strain was sensitive to ceftriaxone. Molecular typing revealed that variants resistant to ESC occurred also among strains belonging to epidemic clonal complex CC1 (genogroup G1407) distinguished in NG-MAST typing system. The G1407 genogroup, in particular the ST1407 sequence type, is currently dominant in most European countries. The presence of different mechanisms of drug resistance significantly affects clinical practice and force changes in treatment regimens and introduction of new drugs.

scholarly journals FKS Mutations and Elevated Echinocandin MIC Values among Candida glabrata Isolates from U.S. Population-Based Surveillance

2010 ◽  
Vol 54 (12) ◽  
pp. 5042-5047 ◽  
Author(s):  
Alicia J. Zimbeck ◽  
Naureen Iqbal ◽  
Angela M. Ahlquist ◽  
Monica M. Farley ◽  
Lee H. Harrison ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Hot Spot ◽  
The United States ◽  
Population Based ◽  
Antifungal Drugs ◽  
Primary Therapy ◽  
Clonal Spread ◽  
High Level ◽  
Single Sequence ◽  
Level Resistance

ABSTRACT Candida glabrata is the second leading cause of candidemia in the United States. Its high-level resistance to triazole antifungal drugs has led to the increased use of the echinocandin class of antifungal agents for primary therapy of these infections. We monitored C. glabrata bloodstream isolates from a population-based surveillance study for elevated echinocandin MIC values (MICs of ≥0.25 μg/ml). From the 490 C. glabrata isolates that were screened, we identified 16 isolates with an elevated MIC value (2.9% of isolates from Atlanta and 2.0% of isolates from Baltimore) for one or more of the echinocandin drugs caspofungin, anidulafungin, and micafungin. All of the isolates with elevated MIC values had a mutation in the previously identified hot spot 1 of either the glucan synthase FKS1 (n = 2) or FKS2 (n = 14) gene. No mutations were detected in hot spot 2 of either FKS1 or FKS2. The predominant mutation was mutation of FKS2-encoded serine 663 to proline (S663P), found in 10 of the isolates with elevated echinocandin MICs. Two of the mutations, R631G for FKS1 and R665G for FKS2, have not been reported previously for C. glabrata. Multilocus sequence typing indicated that the predominance of the S663P mutation was not due to the clonal spread of a single sequence type. With a rising number of echinocandin therapy failures reported, it is important to continue to monitor rates of elevated echinocandin MIC values and the associated mutations.

OPERATIONS FOR ANEURISM OF THE ABDOMINAL AORTIC DEPARTMENT - RESECTION WITH THE FOLLOWING PROSTHETICS AND ENDOPROSTHETICS: A COMPARATIVE ANALYSIS OF COMPLICATIONS

2020 ◽  
pp. 43-49
Author(s):  
Андрей Анатольевич Иванов ◽  
Александр Иванович Жданов ◽  
Максим Сергеевич Шевелин ◽  
Александр Сергеевич Брежнев
Keyword(s):  
Comparative Analysis ◽  
Postoperative Complications ◽  
Statistical Significance ◽  
Aortic Aneurysms ◽  
Surgical Interventions ◽  
Vein Thrombosis ◽  
Scientific Hypothesis ◽  
Abdominal Aortic ◽  
Life Threatening ◽  
High Level

В статье представлены данные оригинального исследования по улучшению хирургического лечения аневризм брюшного отдела аорты. С этой целью произведен сравнительный анализ двух альтернативных друг другу операций: 1) резекции аневризмы с последующим протезированием аорты; 2) эндопротезирования аорты. Сформулировано научное предположение о том, что замена «классических» операций резекции аневризмы на «альтернативные» операции эндопротезирования приведет к принципиальному снижению уровня послеоперационных осложнений. В независимых группах пациентов с использованием сравниваемых хирургических вмешательств произведена точная качественная и количественная оценка послеоперационных осложнений: нетромботических - кардиальных, пульмональных, ренальных и тромботических - тромбозов глубоких вен и тромбозов браншей протеза. После реализации исследования было установлено, что замена «классических» операций на «альтернативные» достоверно приводит к принципиальному снижению уровня наиболее жизнеопасных осложнений - кардиальных (острых форм ишемической болезни сердца, нарушений сердечного ритма), пульмональных (пневмоний, тромбоэмболии легочной артерии, респираторного дистресс-синдрома взрослых) и ренальных (острой почечной недостаточности). Некоторое исключение составили менее жизнеопасные тромботические осложнения. Полученные результаты имеют высокий уровень статистической значимости, что позволяет рекомендовать их к рассмотрению к использованию в практике сосудистой хирургии The article presents data from an original study to improve the surgical treatment of abdominal aortic aneurysms. For this purpose, a comparative analysis of two alternate operations was performed: 1) aneurysm resection followed by aortic prosthetics; 2) aortic endoprosthetics. The scientific hypothesis is formulated that the replacement of the «classical» operations of resection of the aneurysm with «alternative» operations of endoprosthetics will lead to a fundamental decrease in the level of postoperative complications. In independent groups of patients using the compared surgical interventions, an accurate qualitative and quantitative assessment of postoperative complications was made: non-thrombotic - cardiac, pulmonary, renal and thrombotic - deep vein thrombosis and prosthetic jaw thrombosis. After the study was completed, it was found that the fundamental replacement of «classical» operations with «alternative» reliably leads to a fundamental decrease in the level of the most life-threatening complications - cardiac (acute forms of coronary heart disease, cardiac arrhythmias), pulmonary (pneumonia, pulmonary thromboembolism, respiratory distress syndrome of adults) and renal (acute renal failure). Some exceptions were less life-threatening thrombotic complications. The results obtained have a high level of statistical significance, which allows us to recommend them for consideration in the practice of vascular surgery

Efficacy of Novel Schiff base Derivatives as Antifungal Compounds in Combination with Approved Drugs Against Candida Albicans

2019 ◽  
Vol 15 (6) ◽  
pp. 648-658 ◽  
Author(s):  
Manzoor Ahmad Malik ◽  
Shabir Ahmad Lone ◽  
Parveez Gull ◽  
Ovas Ahmad Dar ◽  
Mohmmad Younus Wani ◽  
...  
Keyword(s):  
Schiff Base ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Fungal Infections ◽  
Total Sterol ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Ergosterol Biosynthesis ◽  
Dependent Manner ◽  
Schiff Base Derivatives

Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but also alternative treatment strategies are promptly required. Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates. Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as the rest of the combinations were indifferent. Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies. Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.

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